The present invention relates to a rapamycin 40-O-cyclic hydrocarbon ester, compositions containing the ester, and methods of use of the compound and composition.
Rapamycin is a macrocyclic triene compound that was initially extracted from a streptomycete (Streptomyces hygroscopicus) isolated from a soil sample from Easter Island (Vezina et al., J. Antibiot. 28:721 (1975); U.S. Pat. Nos. 3,929,992; 3,993,749). A variety of rapamycin derivatives designed to improve its solubility, stability, and/or pharmacological profile have been reported. See, for example, Adamczyk et at Lipase Mediated Hydrolysis of Rapamycin 42-Hemisuccinate Benzyl and Methyl Esters, Tetrahedron Letters, Vol. 35, No. 7, pp. 1019-1022, 1994, and U.S. Pat. Nos. 5,258,389, 5,665,772, and U.S. Pat. No. 6,440,990.
One of the major therapeutic uses of rapamycin and its derivatives has been for the treatment of restenosis. Restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a major limitation Manton, M. et al., Drug Therapy, 4:291 301 (1998)). In a typical PTCA procedure, the region of vascular blockage is expanded by balloon angioplasty and a stent is expanded against the vessel walls to maintain the vessel in an expanded diameter state. With a bare metal stent restenosis of the vessel may occur within 3-6 months or more in more than 30% of the cases, requiring additional intervention to restore the vessel to an expanded diameter. Restenosis after PTCA is thought to be a two-component process of both intimal hyperplasia and vascular remodeling, the former coming initially, the latter occurring later in the process (Hoffman. R. et al., Circulation, 94:1247 1254 (1996): Oesterle, S. et al., Am. Heart J., 136:578 599 (1998)).
To reduce the rate of restenosis in a PTCA procedure, the stent may be coated with rapamycin or a rapamycin derivative in a form that allows slow release of the drug from the gent against the endothelial cells of the vessel, typically over a two-week to several-month interval. The stent coating may consist of a polymer, e.g., bioerodable polymer, with encapsulated drug, or the drug itself may form a cohesive coating. In either case, the coating may be susceptible to cracking as the stent is expanded at the implantation site, and any loose pieces of coating that break off can be a significant clotting hazard in the bloodstream. Another problem that has been observed heretofore in rapamycin stents is relatively poor drug stability, as evidence by mass balance measurement on the amounts of active drug released from the stent coatings, typically showing less than 40% of active drug recovered after elution from the stent.